We have previously demonstrated that carbamazepine (CBZ) at concentrations above the therapeutic range is toxic to cultured cerebellar granule cells (CGC). Here, we show that treatment of cultured CGC with CBZ for 3 days resulted in fragmentation of DNA characteristic of apoptosis. N-methyl-D-aspartame (NMDA) blocked CBZ-induced DNA fragmentation and neurotoxicity. Aurintricarboxylic acid (ATA), a polyanionic dye, also markedly suppressed DNA fragmentation and the cell death. Moreover, NMDA and ATA prevented CBZ-induced chromatin condensation. Pre-treatment of cells with cycloheximide, a protein synthesis inhibitor, prevented CBZ- induced neurotoxicity assessed by mitochondrial activity and [3H]ouabain binding assays. Our results suggest that CBZ induces death of CGC by an apoptotic process that is sensitive to NMDA, ATA and cycloheximide. CBZ-induced apoptosis was, however, insensitive to NMDA receptor antagonists, antioxidants and neurotrophins such as BDNF and NT-3. CBZ apoptosis was also associated with a reduction in the mRNA level of glyceraldehyde-3-phosphate dehydrogenase. CBZ neurotoxicity may be the result of inhibition of NMDA receptor-mediated Ca2+ influx. The CBZ inhibition was noncompetitive with respect to NMDA, glycine, and neurosteriods and was facilitated by K+ depolarization. CGC may express a novel type of NMDA receptor that interacts with CBZ. We have also studied the in vivo actions of another psychotropic drug, buspirone. After buspirone treatment of rats, the 5-HT1A receptor mRNA levels were significantly decreased in the CA1 and CA2 of the hippocampus, but were markedly increased in the dentate gyrus (DG), CA3, and CA4. Buspirone treatment markedly increased 5-HT2A receptor mRNA levels in the DG, CA2, CA3, and CA4. This was accompanied by a significant increase in the level of 5-HT2A receptor binding sites in all subhippocampal regions. These results demonstrate that chronic buspirone treatment differentially regulates 5-HT1A and 5-HT2A receptor mRNA as well as their expressed binding sites in various regions of the hippocam- pus.